Cancer may affect people at all ages, but risk tends to increase with age, due to the fact that DNA damage becomes more apparent in aging DNA. It is one of the principal causes of death in developed countries, more than 11 million people are diagnosed with cancer every year, and it is estimated that there will be 16 million new cases every year by 2020. Cancer causes 7 million deaths every year or 12.5% of deaths worldwide. Cancer is a leading cause of death worldwide particularly affecting major portion of people in industrialized world than in the non-industrialized world. From a total of 58 million deaths worldwide in 2005, cancer accounts for 7.6 million (or 13%) of all deaths. The main types of cancer leading to overall cancer mortality are Lung (1.3 million deaths/year), Stomach (almost 1 million deaths/year), Liver (662,000 deaths/year), Colon (655,000 deaths/year) and Breast (502,000 deaths/year). Deaths from cancer in the world are projected to continue rising, with an estimated 9 million people dying from cancer in 2015 and 11.4 million dying in 2030 (Parkin D et al, 2002)
Every cell constantly faces decisions. Should it divide? Or should it differentiate? Or should it die (Apoptosis)? Proper development and tissue homeostasis rely on the correct balance between division and apoptosis. Too much apoptosis leads to tissue atrophy such as in Alzheimer's disease. Too much proliferation or too little apoptosis leads to cancer. Cancer is a disease of multifactorial origin characterized by uncontrolled division of cells; when the cancer cell faces spatial restrictions, due to uncontrolled proliferation in an organ of the body, the ability of the cell to invade other distinct tissues occurs by a process defined as “Metastasis” the stage in which cancer cells are transported through the bloodstream or lymphatic system.
The most common treatment for easily accessible cancer is surgical removal of diseased tissues and radiation. The choice of treatment for in-accessible tumors is chemotherapy. Also chemotherapy is given as additional insurance for most cancer as it is difficult to access the extent of metastasis.
Most clinically revelant anticancer drugs currently used in clinic, interfere with cell division and hence are not highly selective to cancer cells and there are potential chances, that chemotherapy can lead to secondary cancers in due course of time. Also the quality of life is hampered in the patients upon chemotherapy, hence there is an unmet medical need for treating cancer patients without affecting the quality of life. (Hill R P et al., 2005 & Kleinsmith, L J, 2006).
The cell cycle deregulation and the molecular basis of cancer cell growth has been thoroughly exploited in the recent years. Inhibition of signal transduction has become a viable and attractive avenue in biomedical cancer research based on the discovery of a large number of somatic mutations in many different types of cancer that lead to deregulated growth signal transduction and subsequent aberrant growth, invasion, tumor-derived angiogenesis and metastasis. Most of the noncytotoxic drugs that have been recently developed include Protein kinase inhibitors such as Gleevec, Iressa and Tarceva, Tyrosine kinase inhibitors like leflunomide. Glivec™ (STI571), is an inhibitor of the bcr-abl kinase and CML. PKI66, on the other hand, is a dual inhibitor of EGF receptor (HER 1) as well as erbB (HER 2). EGF-receptor and PTK787, potent inhibitors of VEGF-receptor 2 (KDR) are able to suppress tumor growth via suppression of tumor angiogenesis and also these agents have entered clinical trials in tumor patients (Alex Matter, M.D., 2002). These types of orally active and relatively well-tolerated compounds can be used in the clinics; either as single agents or in combination with other well established cytotoxic agents.
Cytokines play an important role in the communication between cells of multicellular organisms. Early studies indicate that B cells lineage tend to secrete IL6 in response to host immune defense mechanisms, but in recent decades studies have indicated elevated levels of IL6 in various cancer phenotypes. IL6 promotes survival and proliferation of certain cancerous cell lines through the phosphorylation of STAT3 (Bharti et al., Verma et al., Kerr et al.). Inhibitors of Jak/Stat pathway likely represent potential therapeutic target for cancer (Catlett Falcone et al., 1999; Alas and Bonavida, 2003; Burdelya et al., 2002)
IL6 has been found to be a growth factor for multiple myeloma cells; anti IL6 antibodies were shown to block myeloma cell proliferation in a leukemic patients (Lkein et al., Blood, 78, (5), pp 1198-1204, 1991 and Lu et al., Eur. J. Immunol., 22. 2819-24, 1992). A need exists for a compound that blocks IL6 mediated Stat3 activation at lower concentration and suppresses expression of proto-oncogene like c-myc, which is overexpressed, rearranged or mutated in many malignancies (Hallek et al., 1998; Selvanayagam et al., 1988; Jernberg-Wiklund et al., 1992; Kuehl et al., 1997).
Elevation of inflammatory cytokine levels, particularly IL-6 and TNF-α also appears to be associated with the Cancer-related cachexia, a syndrome involving loss of adipose and skeletal muscle tissue, and one that is not responsive to increased caloric intake. Cachexia may also be related to the role of acute phase proteins. The acute phase response and production of acute phase proteins (e.g., C-reactive protein [CRP]) are mediated by IL-6. Studies correlate elevated levels of IL-6 elevate acute phase proteins, which, interestingly, are also associated with increased weight loss and decreased survival. Thus, with elevated IL-6 levels, amino acid metabolism is directed away from peripheral tissues to the liver for production of acute phase proteins. This in turn leads to muscle wasting, which is a component of cachexia. Accordingly, the cytokine-induced acute phase response may be a primary component of cancer-related cachexia. Moreover, diminishing or blocking IL-6 activity in animal models attenuates cachexia, further demonstrating the essential role IL-6 plays in the development of this syndrome.
AG490 is a kinase inhibitor that inhibits Jak2/Stat3 signaling. Targeted inhibition of the Jak/Stat pathway with AG490 inhibits tumor cell growth and increases sensitivity to an apoptotic stimulus. AG490 has limited activity in animal studies and must be used at high concentration (˜50-100 μM) to show Jak/Stat3 signaling inhibition and anti-tumor activity (Burdelya et al., 2002; Meydan et al., 1996; Constantin et al., 1998). Thus having an IL6 inhibitory activity, compound may be useful for various inflammatory diseases, sepsis, multiple myeloma, plasmacytoid leukemia, osteoporosis, cachexia, psoriasis, Nephritis, Kaposi's sarcoma, rheumatoid arthritis autoimmune disease, endometriosis and solid cancer (PCT: WO02/074298 A1)
Signal Transducers and Activators of Transcription (STATs):
STAT proteins convey signals from activated cytokines and growth factor receptors to target genes by translocating from the cytoplasm to the nucleus. STAT3 regulates genes involved in cell cycle progression and cell survival, and is commonly hyper-activated in human tumors, suggesting that STAT3 is a validated, and attractive, promising cancer target.
Signal transducers and activators of transcription (STATs) are a family of seven proteins (STATs 1, 2, 3, 4, 5a, 5b, and 6) unique in their ability both to transduce extracellular signals and regulate transcription directly. STATs transduce extracellular signals from cytokines such as interleukin-6 and interferons or growth factors such as platelet-derived growth factor (PDGF) and epidermal growth factor (EGF). Upon activation of these receptors, STATs are recruited to the plasma membrane where they become activated via phosphorylation of conserved tyrosine residues either directly by receptor tyrosine kinases.
In normal cells STAT proteins have been identified as important regulators of diverse physiological functions such as immune response, inflammation, proliferation, differentiation, development, cell survival, and apoptosis (Ihle and Kerr, 1995; Schindler and Darnell, 1995; Horvath and Darnell, 1997; Stark et al., 1998). STAT signaling is tightly regulated in normal cells, either through inhibition of upstream signaling proteins (e.g., internalization of receptors) or negative regulators of Src and JAK proteins, such as SOCS proteins, and Src family and JAK phosphatases (e.g., CD45 and SHP-2) (Irie-Sasaki et al., 2001; Myers et al., 2001; Lefebvre et al., 2003; Lehmann et al., 2003). However, in tumor cells and tissues, disregulation and constitutive activation of STATs, especially STAT3 and STAT5, have been demonstrated to be important to the proliferation and antiapoptotic activity of tumor cells (Bowman and Jove, 1999; Turkson and Jove, 2006).
STATs have been shown to play active roles at all levels of tumorigenesis. STATs are responsible for generating proproliferative signals (e.g., Cyclin D1, survivin; Sinibaldi et al., 2000; Aoki et al., 2003) and have been shown to upregulate antiapoptotic proteins (e.g., Bcl-XL, Bcl-2; Catlett-Falcone et al., 1999).
In addition, STAT3 has been demonstrated to upregulate VEGF expression, which is necessary for angiogenesis and the maintenance of tumor vasculature (Niu et al., 2002). Most tumors cannot sustain their growth unless they are supplied with oxygen and nutrients from newly formed blood vessels. One of the most potent angiogenesis inducing signals is vascular endothelial growth factor (VEGF). This usually produced by cancer cells in higher levels and VEGF binds to a transmembrane receptor tyrosine kinase on endothelial cells, activates endothelial-cell migration and proliferation to form new blood vessels. This STAT3 has been shown to be a direct transcription factor of the VEGF gene. Blocking STAT3 signaling has been shown to inhibit SRC and IL6 induced VEGF upregulation and might therefore also abrogate the induction of VEGF by other tyrosine kinase pathways that lie upstream (Niu et al., Oncogene, 21:2000-2008, 2002 and Wei, D et al., Oncogene 22: 319-329, 2003). Finally, STAT3 has been implicated in the inhibition of immune responses to tumor growth by blocking expression of proinflammatory factors (Wang et al., 2004).
Unregulated activation of STAT3 and STAT5 has been demonstrated in a variety of tumor types, including breast carcinoma, prostrate cancer, melanoma, multiple myeloma, and leukemia among others (Shuai et al., 1996; Garcia et al., 1997, 2001; Catlett-Falcone et al., 1999; Mora et al., 2002; Niu et al., 2002a). The constitutive activation of Stat3 is frequently detected in breast carcinoma cell lines but not in normal breast epithelial cells (Gracia et al., Cell. Growth. Differ. 8:1267 (1997); Bowman et al., Oncogene 19:2474, 2000). It has been reported that approximately 60 percent of breast tumors contains persistently activated STAT3 (Dechow et al., Proc. Natl. Acad. Sci USA 101:10602, 2004).
Activated STAT3 signaling directly contributes to malignant progression of cancer. STAT3 oncogenic function acts through the pro-survival proteins such as Mcl-1, Bcl-2, and BCl-XL and results in the prevention of apoptosis (Real et al., Oncogene 21:7611 (2002); Aoki et al., Blood 101:1535 (2003); Epling-Burnette et al., J. Clin. Invest. 107:351 (2001); Neilsen et al., Leukemia 13:735, 1999).
STAT3 as a molecular target has been further elucidated using an antisense approach (WO 2006/012625 A2) and as a vaccine candidate (WO2004/080394 A2).
Compositions containing STAT3 Decoy Oligonucleotides are useful in treating cancers in which STAT3 is activated, such as squamous cell carcinomas including squamous cell carcinoma of the head and neck (WO 2006/012625 A2).
STAT3 Antagonists and their use as Vaccines against Cancer: Ex vivo immunotherapeutic methods for treating and preventing cancer comprise decreasing STAT3 expression and/or function in tumor cells and the administration of such cells to a subject in need of treatment and/or prevention. This method also comprises activating T-cells by co-culturing the T-cells with the tumor cells with decreased STAT3 expression or function. It further encompasses methods comprising decreasing STAT3 expression or function in antigen-presenting cells and co-administering tumor cells and the antigen presenting cells with decreased STAT3 function to a patient (WO2004/080394 A2).
Atiprimod (N—N-diethl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine) is an orally bioavailable cationic amphiphilic compound which significantly inhibits production of interleukin (IL)-6 and inflammation in rat arthritis and autoimmune animal models. The effect of Atiprimod on human multiple myeloma (MM) cells has been characterized. Atiprimod significantly inhibited growth and induced caspase-mediated apoptosis in drug-sensitive and drug-resistant MM cell lines, as well as patient MM cells. Atiprimod inhibits STAT3 and Akt, but not ERK1/2, phosphorylation triggered by IL-6. It also inhibits NFkB p65 phosphorylation triggered by tumor necrosis factor (TNF-α). Importantly, Atiprimod inhibits both IL-6 and vascular endothelial growth factor (VEGF) secretion in BMSCs triggered by MM cell binding, and also inhibits angiogenesis on human umbilical vein cells (HUVEC). Finally, Atiprimod demonstrates in vivo antitumor activity against human MM cell growth in SCID mice. (Makoto Hamasaki et al, Blood First Edition Online Feb. 10, 2005; DOI 10.1182/blood-2004-09-3794)
Curcumin (chemically diferuloylmethane) a natural compound has been demonstrated as a pharmacologically safe agent in humans, inhibited IL6 induced STAT3 phosphorylation and consequent STAT3 translocation, and thus plays a role in the suppression of proliferation of MM. The constitutive phosphorylation of STAT3 found in certain multiple myeloma cells was also abrogated by the treatment of curcumin. Also this inhibition was reversible. (U.S. 2005/0049299 A1).
Attempts have also been made to inhibit STAT3 upstream regulators such as Janus kinases, especially Jak2 (Blaskovich et al., Cancer Res. 63:1270 (2000). There is a need to develop a small molecule inhibitor of STAT3 based on the structure of STAT3 with high cell permeability, stability that directly blocks STAT3 activation.
Few Prior Art References, which Disclose the Closest Compounds, are Given Here:
i) WO 98/09625 discloses compounds of formula (I) as Selective β3 adrenergic agonists
wherein, X1 is —OCH2—, —SCH2, or a bond; X2 is a bond, or a 1 to 5 carbon straight or branched alkylene; X3 is O, S, or a bond; R1 is a fused heterocycle of the formula
R3 is hydrogen or C1-C4 alkyl; R4 is an optionally substituted heterocycle or a moiety selected from the group consisting of structures cited therein; R5 is hydrogen or C1-C4 alkyl; R6 represents hydrogen, alkyl etc.
ii) U.S. Pat. No. 4,503,067 discloses carbazolyl-(4)-oxypropanolamine compounds of the formula (I)
wherein, R1 is hydrogen, lower alkanoyl or aroyl; R2 is hydrogen, lower alkyl or arylalkyl; R3 is hydrogen or lower alkyl; R4 is hydrogen or lower alkyl, or when X is oxygen, R4 together with R5 can represent —CH2—O—; X is a valency bond, —CH2—, oxygen or sulfur; Ar is mono- or bicyclic aryl or pyridyl; R5 and R6 are individually selected from hydrogen, halogen, hydroxyl, lower alkyl, aminocarbonyl, lower alkoxy, aralkyloxy, lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl; R5 and R6 together can represent methylenedioxy; and the salts thereof with physiologically acceptable acids are outstandingly effective in the treatment and prophylaxis of circulatory and cardiac diseases e.g., hypertension and angina pectoris.
iii) WO 01/62705 discloses compounds of formula (I), as useful amino alcohol derivatives and salts thereof which have gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence and anti-pollakiuria activities,
wherein, X1 is bond or —O(CH2)m- (m is an integral of 1, 2 or 3), X2 is bond, —(CH2)n- or —CH2O—) (n is an integral of 1, 2, or 3) R1 is hydrogen or an amino protective group; R2 is hydrogen, (lower) alkyl or (lower) alkoxy or (lower) alkyl; A is phenyl, pyridyl, indolyl or carbazolyl, each of which may be substituted and B is phenyl or pyridyl each of which may be substituted with one or two substituents selected from the group consisting of halogen, hydroxyl, nitro, etc.; and a pharmaceutically acceptable salt thereof which is useful as a medicament.